It is evident from the literature that millet (little, pearl, proso, foxtail, finger, and kodo millets) whole grains contain antioxidants, reductants, and metal chelators in their soluble and insoluble phenolic extracts. Nevertheless, whole millets may be beneficial as natural antioxidant sources depending on the variety.

There has been great interest in studying the nutraceutical and antioxidant properties of  foxtail millet (FM), pear millet, and finger millet varieties. According to recent studies, FM contains 3.34 mg tocopherol/100 g (wet basis) and 47 mg polyphenols/100. On the other hand, proso millet contains 2.22 mg tocopherol/100 g (wet basis) and 29 mg polyphenolics/100 g ^[1][30].

Currently, over 50 phenolic compounds belonging to several classes, namely, phenolic acids and their derivatives, dehydrotriferulates and dehydrodiferulates, dimers and flavan-3-ol monomers, flavanonols, flavones, and flavonols in four phenolics fractions of several whole millet grains (pearl, little, proso, foxtail, finger, and kodo millets) were positively or tentatively identified using high-performance liquid chromatography (HPLC) and HPLC-tandem mass spectrometry. However, in vitro tests revealed that kodo millet’s insoluble bound fraction showed the highest content of phenols as well as antioxidant activity. In light of this, and based upon published literature data, millet grains can be used as functional food ingredients as well as natural antioxidants ^[2][21].

Several studies have investigated the antioxidant potential of phenolics, and other bioactive components isolated from millet grains and their fractions. It was reported that an ethanol extract of barnyard millet grains contained one serotonin derivative, two flavonoids, and three antioxidative phenolic compounds. Furthermore, Abedin et al. ^[3][31] reported that the methanolic extracts of FM also showed a higher total antioxidant capacity (170 ± 4 mg ascorbic acid equivalents (AAE)/100 g) and total phenolic content (52 ± 2 mg gallic acid equivalents (GAE)/100 g). Additionally, kodo millet flour methanol extracts quenched 1,1,diphenyl-2-picrylhydrazyl (DPPH) by 70% compared to 15% to 53% in other millet extracts. In addition, the white varieties of sorghum, finger millet, and foxtail millet showed lower quenching than their colored counterparts, indicating that phenolics in the seed coat could be responsible for the antioxidant activities. Moreover, compared to wheat, rice, and other millet species, extracts from finger millet were found to have significantly stronger radical-scavenging activity ^[4][32].

Fiber and non-starchy polysaccharides, indigestible carbs that are present in millet, help to lower sugar levels in the blood ^[5][33]. It also has a low glycemic index (GI), which helps to reduce sugar levels in the blood ^[6][34].

A 12-week study with pre-diabetes (64 people) provided similar results. After 6 weeks of FM intervention, fasting blood glucose and glucose after 120 min decreased to 0.3 ± 0.7 mmol/L and 1.0 ± 2.7 mmol/L, respectively. Then both types of glucose remained steady for up to 12 weeks. There was an insignificant difference in fast insulin, fructosamine, and insulin content (after 120 min) throughout the study period. Homeostasis model assessment of insulin resistance (HOMA-IR) significantly decreased from an initial 3.6 ± 2.3 to 2.9 ± 1.7 in the 12th week, on the other hand, HOMA-IR increased from 0.4 ± 0.2 to 0.5 ± 0.6, respectively ^[7][35]. A slight decrease in fasting and post-meal blood sugar insulin resistance was observed by Ren et al. ^[7][35] after taking 50 g of FM/per day. In another study, Shobana et al. ^[8][36] also found lower fasting blood sugar levels and a fall in triglyceride and cholesterol levels in rats with diabetes while feeding them a diet containing 20% finger millet. Moreover, Fu et al. ^[9][37] found that prolamin from cooked foxtail millet (PCFM) ameliorated islet-cell impairment i.e., stimulated insulin secretion as evident from significantly high homeostasis model assessment of β cell function (HOMA-β). HOMA-IR of the model control group (MC) was significantly higher than the normal control group (NC), which indicates insulin resistance. Moreover, the study of Seo et al. ^[10][38] demonstrated that N-p-coumaroyl serotonin, feruloyl serotonin of barnyard millet (Echinochloa utilis) were significantly reduced glucose content (72 and 51% at 0.2 mg/wells) in Caco-2 (human intestinal epithelial) cells and inhibited intestinal sucrase (IC₅₀ of 4.0 and 9 μM) in mammalian rat. Furthermore, it was revealed in a recent study by Krishnan et al. ^[11][39] that pearl millet phenolics inhibit carbolytic enzymes and regulate GLUT and thus have anti-diabetic properties. Similarly, a significant reduction in fasting glucose and insulin levels, as well as HOMA-IR levels, was observed after pearl millet whole grain powder or ethanolic extract administration to obese rats fed a high-fat diet, which supports the hypoglycemic effects of pearl millet ^[12][40]. Moreover, proso millet has been found to improve blood sugar levels and insulin levels in genetically obese type 2 diabetic mice under conditions of high fat intake ^[13][41].

Consumption of millets reduces hyperlipidemia and raises the levels of high-density lipoprotein cholesterol (HDL-C), according to a recent systematic review and meta-analysis of the impacts of millets consumption on lipid profile, including triglyceride (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), HDL-C, and very-low-density lipoprotein cholesterol (VLDL-C). Consuming millets for periods ranging from 21 days to 4 months was shown to reduce levels of TC, TG, LDL-C, and VLDL-C by 8.0, 9.5, 10, and 9.0%, respectively, according to the findings of 19 research. Researchers in four separate investigations found that consuming millets resulted in normal levels of TG and TC (>150 and >200 mg/dl, respectively). Additionally, the HDL-C 4.0 increased by 6.0% after eating millet-based meals ^[14][42].

Lee et al. ^[15][43] found reduced triglyceride, compared with the control group that those fed foxtail and proso millet in rats. Additionally, millet protein may help lower cholesterol, which was claimed by Nishizawa et al. ^[16][44].

Choi et al. ^[17][45] found foxtail millet protein (FMP) diet group had a significantly higher total plasma cholesterol concentration than the casein diet group. HDL-C concentration in the FMP diet group was more than twice that of the casein diet group. The plasma insulin concentration of the FMP diet group was reduced by 57% in contrast to the casein diet, without any significant difference in plasma glucose concentration. The plasma adiponectin concentration of the FMP diet group was 64% greater than that of the casein diet group. In the liver, the concentration of cholesterol declined significantly in the case of the FMP diet when compared with that of the casein diet, but triglyceride content was greater in the FMP diet group. The plasma triglyceride content of the casein diet group was found to be significantly lower than the FMP diet group. HDL-cholesterol in the plasma of the casein diet group was significantly lower than the FMP diet group. Plasma glucose concentration was similar; however, insulin concentration in the FMP diet group was lower than in the casein diet group. The FMP diet group contained almost twice the plasma adiponectin than the casein diet group. Liver cholesterol concentrations were significantly lower for the FMP diet than the casein diet, but triglyceride content was similar.

Molla M. M., ^[18][23] found millet protein diets such as uncooked extracted (UCE), cooked extracted (CE), uncooked extracted enriched (UCEE), and cooked extracted enriched (CEE) groups significantly reduced the plasma and liver TC, TG, and LDL-C than uncooked (UC) and cooked FM (C FM) flour diets, in casein, control, and normal diet group. It also significantly increased the plasma HDL-C compared to UC and C FM flour diets, casein, control, and normal diets. These results are strongly supported by Choi et al. ^[17][45]; Park et al. ^[13][41]; Nishizawa et al. ^[16][44]. UCE and UCEE FM protein diets increased the plasma HDL-C and reduced the plasma and liver TC, TG, and plasma LDL-C in comparison with other diets. Cholesterols lowering effects might be the result of antinutritional richness in the UCE and UCEE FM protein diet than other diets ^[19][46]. Higher antinutrients might help to reduce cholesterol levels, and the risk of stroke, coronary heart disease, certain cancer, and liver disorder through their antioxidant activity ^[20][47].

Millet protein (FM) increased the plasma HDL-C level whereas, decreased the plasma TC, TG, and LDL-C and liver TC and TG, which may be a good predictor to reduce the risk of liver injury and hyperlipidemia ^[18][23]. These outcomes are parallel to the findings of Choi et al. ^[17][45] who reported that Korean foxtail millet protein has a protective action for reducing atherosclerosis by increasing the HDL-C level. Nishizawa et al. ^[21][48] reported that proso millet protein supplemented with lysine and threonine have a favorable effect on cholesterol metabolism by elevating plasma HDL-C level and lowering LDL-C, TC, and TG level for both plasma and liver which is inversely related to the risk of coronary heart disease.

Ren et al. ^[7][35] found that after 12 weeks millet (FM) interventions, diastolic blood pressure (DBP) declined significantly from 84.9 ± 8.5 mmHg to 81.6 ± 7.8 mmHg. Hou et al. ^[22][49] found both systolic blood pressure (SBP) and DBP decreased significantly due to 12 weeks millet (FM) diet intervention from the initial (133.61 ± 1.94 mmHg) to 12th week (129.48 ± 2.14 mmHg). On average, SBP and DBP were reduced by 4.13 mmHg and 3.49 mmHg, respectively. Dietary fiber, protein, and minerals in whole grains are inversely associated with blood pressure (BP) ^[23][50]. FMP hydrolysates may significantly decrease BP in hypertensive rats ^[24][51]. Studies have revealed that phytochemicals in millet possess serum lipid-reducing properties ^[25][52]. Chen et al. ^[24][51] observed SBP declined significantly after 4 weeks of millet intervention, compared to the control (194.9 ± 3.5 mmHg). Whereas it was found 167.4 ± 2.5, 166.3 ± 3.5, 168.4 ± 6.3, and 179.0 ± 5.0 mmHg in captopril, raw foxtail millet protein hydrolysates (RPH), extruded foxtail millet protein hydrolysates (EPH), and fermented foxtail millet protein hydrolysates with R. oryzae (FRPH), respectively. SBP persistently declined in RPH, EPH, and captopril groups, except the FRPH group. The reduction was observed to be higher in the RPH (28.3 mmHg), EPH (24.8 mmHg), and captopril (23.6 mmHg) treatment groups, but in the FRPH group, it was only 13.6 mmHg.

Chen et al. ^[24][51] found reduced serum angiotensin-converting enzyme (ACE) activity significantly after 4 weeks of intervention in the control group (141.8 ± 14.6 U/L). For other treatments the values were; RPH (104.1 ± 7.4 U/L), FRPH (85.5 ± 16 U/L), EPH (88.9 ± 15.5 U/L), and captopril (95.2 ± 13.6 U/L). Additionally, a non-significant difference was detected between the three FMP hydrolysate groups and the captopril group. Plasma angiotensin II (Ang II) levels in control were 2.85 ± 0.29 ng/mL, which declined significantly when treated with FRPH (1.75 ± 0.42 ng/mL), RPH (1.68 ± 0.48 ng/mL), captopril group (1.50 ± 0.56 ng/mL) and EPH (1.44 ± 0.31 ng/mL).

Hou et al. ^[26][53] found the levels of Ang II, aldosterone, and ACE exhibited a downward drift during the study period. The antihypertensive effects of whole grains seem to be developed from better endothelial activity, which combined actions of several intrinsic factors such as obstructing the vasoconstrictors effect, induction of vasodilation, affecting vasorelaxation pathways. Chen et al. ^[24][51] indicated millet diets have an anti-hypertensive effect, resulting from the inhibition of serum ACE activity. He also found that ACE, Ang II, and aldosterone in serum declined, demonstrating a probable antihypertensive mechanism of millet inhibition of ACE activity with slight hypertension.

UCE and UCEE FM protein diet may have antioxidant activities, that are believed to break up the free radical chain of oxidation and donate hydrogen thereby lowering the cholesterol level. Therefore, it is said that FM protein has a protective action against degenerative diseases such as heart disease, stroke, liver disorders, and cancer ^[27][54].

Reactive oxygen species (ROS) are facilitators of cellular injury and play a vital role in hepatic damage in the case of D-galactosamine-induced hepatitis. This elimination of ROS in the liver is accelerated by the non-essential amino acid proline which is higher in the UCE and UCEE FM protein diet ^[28][55]. Millet (FM) protein diet is capable to suppress the hepatotoxicity of D-galactosamine-induced acute liver injury ^[29][56].

Intake of millet decreased body weight, body mass index (BMI), and degree of obesity. Body fat mass of 22.1 ± 7.1 kg declined to 21.1 ± 6.2 kg, which appears to be parallel to the body weight variation of initial 69.1 ± 11.6kg to final 68.2 ± 11.2 kg ^[7][35].

Choi et al. ^[17][45] could not find any significant variation in weight gain, epididymal adipose tissue weight, or plasma triglyceride concentration between the two dietary groups, but the liver weight was higher in the FMP diet group than that of the group fed with the casein diet.

Although there was no significant difference in body weight (BW) gain or liver weight between the two dietary groups, the epididymal adipose tissue weight was significantly lower in the FMP group than in the casein group.

Hou et al. ^[22][49] found that millet significantly reduced BMI, body fat percentage (BF%), body fat mass, and waist circumference (WC) during the study period, whereas the circumferences of the hip increased. Waist-hip ratio closely stayed constant. Higher BP might decrease bone density, eventually causing osteoporosis. The primary key to measuring and monitoring any intervention treatment is weight loss. BMI reduced significantly at 12 weeks of the study, which advised that millet might lessen BP secondarily by decreasing obesity degree. Body weight is intensely linked with hypertension, any upsurge in BW rises body fluid and peripheral resistance ^[30][57].

Chen et al. ^[24][51] found body weight of spontaneously hypertensive rats usually increased with age, but among the treatment groups, the difference was insignificant. Considering heart weight (%) in the control group (0.50 ± 0.03 g/100 g BW), it was significantly lower in captopril (0.41 ± 0.02 g/100 g BW), RPH (0.43 ± 0.01 g/100 g BW), EPH (0.40 ± 0.01 g/100 g BW), and FRPH (0.41 ± 0.01 g/100 g BW).

Fu et al. ^[9][37] found a steady BW increase in the NC group, while it decreased significantly in the MC group, which is considered a classic diabetes indicator. BW of mice increased slightly after 5 weeks of treatments with millet (PCFM), which advocated that millet intervention might inhibit diabetic BW loss. The PCFM group exhibited significantly lower fasting blood glucose (FBG) than the MC group, though it was still significantly higher than the NC group.

The millet diet (UCE and UCEE FM protein) significantly reduced body weight as compared to other diets ^[18][23]. The reason may be a lower gain of final body weight by the UCE and UCEE FM protein diet over the whole study period than other diets. High protein intake can contribute to losing weight more than other diets ^[31][58]. Lower energy intake associated with IIP intake possibly contributes to weight loss more than other low-protein diets ^[32][59]. It is also well reported that millet (FM) protein contains more fiber, antioxidants, and phenolic compounds which may contribute to lower body weight ^[33][60]. Liver and relative liver weight was significantly increased by the UCE, UCEE, and CEE FM protein diet than other diets ^[32][59].

Fu et al. ^[9][37] found Firmicutes and Bacteroides two major phyla in the gut microbiota, and their ratio (Bacteroides (B)/Firmicutes (F)) is positively related to plasma glucose level. MC group demonstrated significantly lower B/F than the NC group, which caused a higher level of FBG. Millet intervention slightly amplified the B/F ratio, though the dissimilarity witnessed between MC and PCFM groups was non-significant. Overall, at the phylum level in gut microbiota, millet administration has a non-significant effect. However, the PCFM group contained higher Odoribacter than the MC group. The relative abundance of the above-mentioned bacteria was changed by PCFM, which might be associated with the anti-diabetic effect. PCFM group also contained a higher amount of Blautia, Akkermansia and Odoribacter compared to NC and MC groups.

Molla M.M., ^[18][23] found a higher abundance of Bacteroidetes in the casein diet followed by the normal and control diet and that may be due to a high number of Prevotella and Bacteroides, increasing the inflammation. Inflammation involves chronic liver diseases and develops progressive hepatic damage and fibrosis. It has been reported that Lactobacellus rhamnosus, Lactobacillus salivarius or Pediococcus pantosaceus prevent D-galactosamine-induced liver injury ^[34][61]. Firmicutes are more dominant bacteria in the UC FM diet than in the C FM diet. In contrast, Bacteroidetes predominate in the C FM diet followed by Firmicutes. The higher abundance of the UC FM diet was largely due to a high number of Allobaculum genus and Lactobacillus genus at the phylum level of Firmicutes than the C FM diet. Butyric acids have been reported to play a crucial role in upholding gut health, the energy source to the colonic mucosa, a regulator of gene expression, regulation, differentiation, and apoptosis in host cells ^[35][62]. Providing a UC FM diet could upsurge the bacterial production of butyric acids in the large intestine. These results are supported by the findings of Louis et al. ^[36][63]. The resistant starch or high protein diet provides an energy source for gut microbiota, which has been proposed as a potential prodrug for treating inflammatory bowel disease (IBD) and decrease DNA damage ^[37][64]. On the other hand, the higher abundance of Bacteroidetes in the C FM diet may be due to the higher presence of Prevotella genus which has been reported to cause various diseases ^[38][65]. Bacteroidetes was the most abundant phylum in the CE FM protein diet followed by Firmicutes. The increase in Firmicutes involves producing several butyrate microbes, which have several health-beneficial effects ^[36][63].

However, the microbiome of the UCE FM protein diet contained a high proportion of Firmicutes and a low proportion of Actinobacteria. Murphy et al. ^[39][66] reported that a relative increase in Firmicutes and a decrease in Actinobacteria levels could contribute to lower blood glucose, TNF-ɑ, and triglyceride levels. Costa et al. ^[40][67] stated Firmicutes dominated followed by Bacteroidetes. Similar findings also have been made by Middelbos et al. ^[41][68] in dogs upon supplementation with dietary fiber. On the other hand, the UCE FM protein diet had higher Proteobacteria, while the CE FM protein diet had lower. The high abundance of Proteobacteria in the UCE FM protein diet may be due to a high number of Sutterella geniuses in the phylum of Proteobacteria. In the CE FM protein diet, the abundance is high due to the higher number of Bacteroides at the phylum level of Bacteroidetes. Bacteroides with high abundance has been reported to influence inflammation, liver injury, and regeneration ^[42][69].

In the CEE and UCEE FM protein diet, Bacteroidetes was the most abundant phylum with high abundance in CEE FM protein diet followed by Firmicutes, Verrucomicrobia, Proteobacteria, and Actinobacteria. In contrast, the presence of Verrucomicrobia and Firmicutes was greater followed by Bacteroidetes, Actinobacteria, and Proteobacteria in the UCEE FM protein diet. The high abundance of Bacteroidetes in the CEE FM protein diet may be due to a high number of Prevotella genus. An increase in the Prevotella genus at the phylum of Bacteroidetes might result in periodontal disease, human alcoholic liver disease, and IBD in patients ^[43][70]. Prevotellaceae might produce sulfatases that disrupt the mucosal barrier function; these enzymes are elevated in intestinal biopsies from IBD patients ^[44][71]. Higher Verrucomicrobia might be due to a high number of Akkermansia genus in the UCEE FM protein diet. It has been reported that Akkermansia is a much degrading bacterium in the mucus layer ^[29][56]. The presence of this bacterium is contrariwise related to body weight and type-2 diabetes. Data shows that the UCE FM protein diet led to the relative increase in Firmicutes and Proteobacteria compared with another phylum of Bacteria, in control and other diets.